Evidence now supports the hypothesis that many forms of immune complex nephritis result from initial glomerular localization of exogenous antigens followed by in situ immune deposit formation. This project will fulrther define the factors which regulate this process, with emphasis on in situ subeptihelial immune depost formation with exogenous antigens. It will also explore the thesis that the mediation of glomerular injury, and type of lesion produced, is as much dependant on the site of immune deposit formation within the glomerulus as on the nature of the immune reactants involved. In sity subepithelial immune deposit formation with exogenous antigens will be studied employing a model in which a non-nephritogenic IgG fraction of sheep antibody to rat proximal tubular epithelial cell brush border (Fx1A) is immunologically "planted" as antigen in the subepithelial space. To avoid the formation of curculating immune complexes, such kidneys will be transplanted into rats subsequently injected with affinity-purified anti-sheep IgG antibodies of defined size, charge, avidity and complement-fixing ability. We will define the role of complement, neutrophils and other mediators in producing the proteinuria which results from antigen-antibody interaction at a subepiethelial site, establish the influence of alterations in the quantity and charge of the planted antigen on development of this lesion and define the effect of alterations in antibody size, charge and avidity on the in situ development of subepithelial immune deposits. Radiolabelling will permit accurate quantitation of both antigen and antibody components of glomerular immune deposits in these studies. The effect of changes in the site of immune deposit formation on the mediators involved and glomerular lesion produced, will be studied by using a known quantity of an antigen (sheep IgG) planted in the suepithelial space (as anti-Fx1A), within the GBM (as anti-GBM antibody) and in the mesangium (as heat-aggregated IgG) of transplated kidneys subsequently exposed to equivalent amounts of glomerular fixing anti-sheep IgG in the recipient. These studies will provide a comprehensive analysis of the mechanisms, mediators and consequences of in situ glomerular immune deposit formation at most sites where this newly appreciated process seems likely to participate in causing human renal disease.